Alzheimer's disease is the fourth leading cause of death in the United States after heart disease, cancer and stroke. It is characterized by a progressive loss of cognitive function, neurodegeneration and an accumulation of amyloid plaques in the brains of patients. Although generally considered a disease of the elderly, an early onset familial form of Alzheimer's disease has been identified and associated with mutations in two genes, presenilin-1 and presenilin-2 (Sherrington, et al., Nature 375:754-760 (1995); Rogaev, et al., Nature 376:775-778 (1995); Levy-Lahad, et al., Science 269:970-973 (1995); Hiltunen, et al., Eur. J. Hum. Genet. 8:259-266 (2000); Jonghe, et al., Hum. Mol. Genet. 8:1529-1540 (1999); Tysoe, et al., Am. J. Hum. Genet. 62:70-76 (1998); Crook, et al., Nat. Med. 4:452-455 (1998)). In general, it is believed that mutations in these genes lead to an increase in the formation and aggregation of amyloid protein which, in turn, causes neuronal disruption and death (Duff, et al., Nature 383:710-713 (1996); Scheuner, et al., Nature Med. 2:864-870 (1996); Borchelt, et al., Neuron 17:1005-1013 (1996)). While this prevailing view posits that pathogenic presenilin mutations cause Alzheimer's disease via a toxic gain-of-function mechanism, it remains possible that such mutations may confer a partial loss of presenilin function.
Previous studies conducted on PS1−/− mice revealed an essential role for PS1 in neurogenesis and cortical development, but mutant mice displayed perinatal lethality due to skeletal defects (Shen, et al., Cell 89:629-639 (1997)). Although PS2−/− mice are viable and phenotypically normal (Donoviel, et al., Genes & Dev. 13:2801-2810 (1999); Herreman, et al., Proc. Natl. Acad. Sci. USA 96:11872-11877 (1999); Steiner, et al., J. Biol. Chem. 274:28669-28673 (1999)), mice that lack both presenilins (PS−/−) exhibit early embryonic lethality and severe early patterning defects indicating functional redundancy between PS1 and PS2 (Donoviel, et al., Genes & Dev. 13:2801-2810 (1999)).
In order to circumvent the early demise of PS1−/− mice, the Cre/loxP recombination system has been used to generate conditional knockout (cKO) mice in which the expression of PS1 is selectively eliminated in excitatory neurons of the forebrain beginning about at postnatal day 18 (Yu, et al., Neuron 31:713-726 (2001)). In contrast to the striking brain phenotypes observed in PS1−/− mice, PS1 cKO mice were found to exhibit only a subtle deficit in spatial memory, whereas synaptic transmission and plasticity are normal. Thus, the mice do not exhibit the broad range of progressive cognitive impairments characteristic of Alzheimer's disease. One possibility for these results is that presenilin-2 may be largely compensating for the deficiency in presenilin-1 activity and thereby masking a causal relationship between a loss of presenilin function and the development of age-dependent neuronal degeneration.